One of the most important and fundamental processes in biology is the division of cells mediated by the cell cycle. This process ensures the controlled production of subsequent generations of cells with defined biological function. It is a highly regulated phenomenon and responds to a diverse set of cellular signals both within the cell and from external sources. A complex network of tumor promoting and suppressing gene products are key components of this cellular signaling process. Over expression of the tumor promoting components or the subsequent loss of the tumor suppressing products will lead to unregulated cellular proliferation and the generation of tumors (Pardee, Science 246:603-608, 1989).
Cyclin dependent kinases (cdks) play a key role in regulating the cell cycle machinery. These complexes consist of two components: a catalytic subunit (the kinase) and a regulatory subunit (the cyclin). To date, nine kinase subunits (cdk 1-9) have been identified along with several regulatory subunits (cyclins A-H) (A. M. Senderowicz and E. A. Sausville Journal of the National Cancer Institute (2000), 92 (5), 376-387; S. Mani; C. Wang; K. Wu; R. Francis; R. Pestell Exp. Opin. Invest. Drugs (2000) 9(8), 1849-1870; Brizuela, Leonardo; Gyuris, Jeno; Mansuri, Muzammil, Princ. Mol. Oncol. (2000), 197-236; Fry, David W.; Garrett, Michelle Curr. Opin. Oncol., Endocr. Metab. Invest. Drugs (2000), 2(1), 40-59).
Each kinase associates with a specific regulatory partner and together make up the active catalytic moiety. Each transition of the cell cycle is regulated by a particular cdk complex: G1/S by cdk2/cyclin E, cdk4/cyclin D1 and cdk6/cyclinD2; S/G2 by cdk2/cyclin A and cdk1/cyclin A; G2/M by cdk1/B. The coordinated activity of these kinases guides the individual cells through the replication process and ensures the vitality of each subsequent generation (Sherr, Cell 73:1059-1065, 1993; Draetta, Trends Biochem. Sci. 15:378-382, 1990)
An increasing body of evidence has shown a link between tumor development and cdk related malfunctions. Over expression of the cyclin regulatory proteins and subsequent kinase hyperactivity have been linked to several types of cancers (Jiang, Proc. Natl. Acad. Sci. USA 90:9026-9030, 1993; Wang, Nature 343:555-557, 1990). More recently, endogenous, highly specific protein inhibitors of cdks were found to have a major affect on cellular proliferation (Kamb et al, Science 264:436-440, 1994; Beach, Nature 336:701-704, 1993). These inhibitors include p16.sup.INK4 (an inhibitor of cdk4/D1), p21.sup.CIP1 (a general cdk inhibitor), and p27.sup.KIP1 (a specific cdk2/E inhibitor). A recent crystal structure of p27 bound to cdk2/A revealed how these proteins effectively inhibit the kinase activity through multiple interactions with the cdk complex (Payletich, Nature 382:325-331, 1996). These proteins help to regulate the cell cycle through specific interactions with their corresponding cdk complexes. Cells deficient in these inhibitors are prone to unregulated growth and tumor formation.
Protein kinases, in particular, CDK, play a role in the regulation of cellular proliferation. Therefore, CDK inhibitors could be useful in the treatment of cell proliferative disorders such as cancer, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, fungal infections, endotoxic shock, trasplantaion rejection, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis (U.S. Pat. No. 6,114,365).
CDKs are also known to play a role in apoptosis. Therefore CDK inhibitors, could be useful in the treatment of useful of cancer; viral infections, for example, herpevirus, poxyirus, Epstein-Barr virus, Sindbis virus and adenovirus; prevention of AIDS development in HIV-infected individuals; autoimmune diseases, for example, systemic lupus, erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus; neurodegenerative disorders, for example, Alzheimer's disease, AIDS-relateddementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration; myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases, for example, chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system, for example, osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain (U.S. Pat. No. 6,107,305).
It has also been discovered that some cyclin-dependent kinase inhibitors can be used in combination therapy with other anticancer agents. For example, the cytotoxic activity of the cyclin-dependent kinase inhibitor, flavopiridol, has been used with other anticancer agents in cancer combination therapy. Cancer Research, 57, 3375 (1997).
Also, it has recenly been disclosed that CDK inhibitors may be useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse (U.S. Pat. No. 6,107,305).
Furthermore, it has recently been discovered that cdk5 is involved in the phosphorylation of tau protein, and therefore CDK inhibitors may be useful in the treatment of Alzheimer's disease (J. Biochem., 117, 741-749, 1995).
This body of evidence has led to an intense search for small molecule inhibitors of the cdk family as an approach to cancer chemotherapy. There are no known examples of molecules related to the current invention which describe 5-substituted-indeno[1,2-c]pyrazoles as cdk inhibitors. There is one case describing indeno[1,2-c]pyrazoles having anticancer activity. There are two other examples which describe indeno[1,2-c]pyrazoles having unrelated utilities and structures.
A series of indeno[1,2-c]pyrazoles having anticancer activity are described in JP 60130521 and JP 62099361 with the following generic structure: ##STR2##
No substitution is claimed on the indenophenyl portion of the molecule and the molecules are not indicated to be cdk inhibitors. In addition, we discovered that substitution at the 5-position was critical for cdk inhibitory activity.
A series of indeno[1,2-c]pyrazoles having herbicidal activity are described in GB 2223946 with the following generic structure: ##STR3##
wherein X.sub.n is defined as halo, alkyl, haloalkyl, and haloalkoxy; n=0-2. In addition, R.sub.1 is defined as acyl and R.sub.2 is defined as alkyl or cycloalkyl. PA1 wherein R.sup.1, R.sup.2, R.sup.5 and X are defined below or pharmaceutically acceptable salts thereof are cyclin dependent kinase inhibitors. PA1 X is O or S; PA1 R.sup.1 is --NR.sup.3 R.sup.3a, --CF.sub.3, C.sub.1-4 alkyl substituted with 1-3 R.sup.4, C.sub.5-10 alkyl substituted with 0-3 R.sup.4, C.sub.2 -C.sub.10 alkenyl substituted with 0-3 R.sup.4, C.sub.2 -C.sub.10 alkynyl substituted with 0-3 R.sup.4, C.sub.3 -C.sub.10 carbocycle substituted with 0-5 R.sup.6, or 5-10 membered heterocycle substituted with 0-3 R.sup.6 ; PA1 provided that if R.sup.1 is phenyl or benzyl, then R.sup.1 is substituted with 1-5 R.sup.6 ; PA1 R.sup.2 is H, C.sub.1-10 alkyl substituted with 0-3 R.sup.7, C.sub.2-10 alkenyl substituted with 0-3 R.sup.7, C.sub.2-10 alkynyl substituted with 0-3 R.sup.7, --CF.sub.3, C.sub.3-10 carbocycle substituted with 0-5 R.sup.8, or 3-10 membered heterocycle substituted with 0-5 R.sup.8 ; PA1 R.sup.3 and R.sup.3a are independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; PA1 R.sup.4 and R.sup.7 are, at each occurance, independently selected from the group: halo, --CN, NO.sub.2, --NR.sup.9 R.sup.9a, NR.sup.9 NR.sup.9a R.sup.9b, NR.sup.9 C(O)OR.sup.10, NR.sup.9 C(O)R.sup.10, .dbd.O, OR.sup.10, SR.sup.10, --CF3, COR.sup.10, CO.sub.2 R.sup.10, CONR.sup.9 R.sup.9a, NHC(O)NR.sup.9 R.sup.9a, NHC(S)NR.sup.9 R.sup.9a, SO.sub.2 NR.sup.9 R.sup.9a, SO.sub.2 R.sup.10, C.sub.3-10 carbocycle substituted with 0-5 R.sup.11, and 5-10 membered heterocycle substituted with 0-3 R.sup.11 ; PA1 R.sup.5 is selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; PA1 R.sup.6 and R.sup.8 are, at each occurance, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14,--CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, SO.sub.2 R.sup.14, C.sub.3-10 carbocycle substituted with 0-5 R.sup.15, and 5-10 membered heterocycle substituted with 0-3 R.sup.15, or when two R.sup.6s or R.sup.8s are attachd to two adjacent carbon atoms, the two R.sup.6s or R.sup.8s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; PA1 R.sup.9 is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; PA1 R.sup.9b is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; or PA1 R.sup.9 and R.sup.9a, together with the nitrogen atom to which they are attached, form a heterocycle substituted with 0-3 R.sup.16 ; PA1 R.sup.9a is selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; PA1 R.sup.10, R.sup.14, R.sup.17 are, at each occurance, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, benzyl; PA1 R.sup.11 is, at each occurance, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.18 R.sup.18a, NR.sup.18 NR.sup.18a R.sup.18b, NR.sup.18 C(O)OR.sup.17, NR.sup.18 C(O)R.sup.17, .dbd.O, OR.sup.17, SR.sup.17, COR.sup.17, CO.sub.2 R.sup.17, CONR.sup.18 R.sup.18a, NHC(O)NR.sup.18 R.sup.18a, NHC(S)NR.sup.18 R.sup.18a, SO.sub.2 NR.sup.18 R.sup.18a, SO.sub.2 R.sup.17, C.sub.3-10 carbocycle substituted with 0-5 R.sup.19, and 5-10 membered heterocycle substituted with 0-3 R.sup.19 ; PA1 R.sup.13 is is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; PA1 R.sup.13a is, at each occurance, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; or PA1 R.sup.13 and R.sup.13a, together with the nitrogen atom to which they are attached, form a heterocycle substituted with 0-3 R.sup.16 ; PA1 R.sup.13b is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; PA1 R.sup.15, R.sup.16 and R.sup.19 are, at each occurance, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.20 R.sup.20a, NR.sup.20b NR.sup.20 R.sup.20a, NR.sup.20 C(O)OR.sup.21, NR.sup.20 C(O)R.sup.21, .dbd.O, OR.sup.21, SR.sup.21, COR.sup.21, CO.sub.2 R.sup.21, CONR.sup.20 R.sup.20a, NHC(O)NR.sup.20 R.sup.20a, NHC(S)NR.sup.20 R.sup.20a, SO.sub.2 NR.sup.20 R.sup.20a, SO.sub.2 R.sup.21, or when two R.sup.15 s, R.sup.16 s or R.sup.19 s are attachd to two adjacent carbon atoms, the two R.sup.15 s R.sup.16 s or R.sup.19 s may combine to form --OCH2O--or --OCH2CH2O--; PA1 R.sup.18 is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; PA1 R.sup.18a is, at each occurance, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl;or PA1 R.sup.18 and R.sup.18a, together with the nitrogen atom to which they are attached, form a heterocycle substituted with 0-3 R.sup.19 ; PA1 R.sup.18b is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; or PA1 R.sup.20 is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; PA1 R.sup.20a is, at each occurance, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; PA1 R.sup.20b is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; and PA1 R.sup.12 and R.sup.21 are, at each occurance, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, benzyl; or PA1 X is O or S; PA1 R.sup.1 is --NR.sup.3 R.sup.3a, --CF.sub.3,C1-C4 alkyl substituted with 1-3 R.sup.4, C.sub.2 -C.sub.4 alkenyl substituted with 0-3 R.sup.4, C.sub.2 -C.sub.4 alkynyl substituted with 0-3 R.sup.4, C.sub.3 -C.sub.10 carbocycle substituted with 0-5 R.sup.6, or 5-10 membered heterocycle substituted with 0-3 R.sup.6. PA1 X is O or S; PA1 R.sup.1 is --NR.sup.3 R.sup.3a, --CF.sub.3, C1-C4 alkyl substituted with 1-3 R.sup.4, C.sub.2 -C.sub.4 alkenyl substituted with 0-3 R.sup.4, C.sub.2 -C.sub.4 alkynyl substituted with 0-3 R.sup.4, C.sub.3 -C.sub.6 carbocycle substituted with 0-5 R.sup.6, or 5-7 membered heterocycle substituted with 0-3 R.sup.6. PA1 R.sup.1 is C.sub.3 -C.sub.6 saturated carbocycle substituted with 0-5 R.sup.6, or 5-7 membered saturated heterocycle substituted with 0-3 R.sup.6. PA1 R.sup.1 is C.sub.5 -C.sub.6 partially saturated carbocycle substituted with 0-5 R.sup.6, or 5-7 membered partially saturated heterocycle substituted with 0-3 R.sup.6. PA1 R.sup.1 is phenyl substituted with 1-5 R.sup.6, naphthyl substituted with 0-5 R.sup.6, or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.6. PA1 R.sup.1 is phenyl substituted with 1-3 R.sup.6, naphthyl substituted with 0-3 R.sup.6, or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.6. PA1 R.sup.1 is C.sub.3 -C.sub.10 carbocycle substituted with 0-5 R.sup.6, or 5-10 membered heterocycle substituted with 0-3 R.sup.6 ; PA1 R.sup.6 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.6s are attached to two adjacent carbon atoms, the two R.sup.6s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--. PA1 R.sup.6 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.6s are attached to two adjacent carbon atoms, the two R.sup.6s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; PA1 R.sup.13, R.sup.13a and R.sup.13b are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; and PA1 R.sup.14 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, and benzyl. PA1 R.sup.6 is independently at each occurrence selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14 ; PA1 R.sup.13, R.sup.13a and R.sup.13b are each independently selected from the group: H or methyl; and PA1 R.sup.14 is independently selected from the group: H, methyl, phenyl, and benzyl. PA1 X is O or S; PA1 R.sup.1 is --NR.sup.3 R.sup.3a, --CF.sub.3, C1-C4 alkyl substituted with 1-3 R.sup.4 ; PA1 R.sup.4 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, --NR.sup.9 R.sup.9a, NR.sup.9 NR.sup.9a R.sup.9b, NR.sup.9 C(O)OR.sup.10, NR.sup.9 C(O)R.sup.10, .dbd.O, OR.sup.10, SR.sup.10, --CF3, COR.sup.10, CO.sub.2 R.sup.10, CONR.sup.9 R.sup.9a, NHC(O)NR.sup.9 R.sup.9a, NHC(S)NR.sup.9 R.sup.9a, SO.sub.2 NR.sup.9 R.sup.9a, and SO.sub.2 R.sup.10 ; PA1 R.sup.9 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; PA1 R.sup.9a is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; PA1 R.sup.9b is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; or PA1 R.sup.9 and R.sup.9a, together with the nitrogen atom to which they are attached, form a 5-7 membered heterocycle substituted with 0-3 R.sup.16 ; PA1 R.sup.16 is, at each occurrence, independently selected from the group consisting of: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.20 R.sup.20a, NR.sup.20b NR.sup.20 R.sup.20a, NR.sup.20 C(O)OR.sup.21, NR.sup.20 C(O)R.sup.21, .dbd.O, OR.sup.21, SR.sup.21, COR.sup.21, CO.sub.2 R.sup.21, CONR.sup.20 R.sup.20a, NHC(O)NR.sup.20 R.sup.20a, NHC(S)NR.sup.20 R.sup.20a, SO.sub.2 NR.sup.20 R.sup.20a, and SO.sub.2 R.sup.21 ; and PA1 R.sup.20, R.sup.20a, and R.sup.20b are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl. PA1 X is O or S; PA1 R.sup.1 is --NR.sup.3 R.sup.3a, --CF.sub.3, C1-C4 alkyl substituted with 1-3 R.sup.4 ; PA1 R.sup.3 and R.sup.3a are independently selected from the group: H, methyl, phenyl and benzyl; PA1 R.sup.4 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, --NR.sup.9 R.sup.9a, NR.sup.9 NR.sup.9a R.sup.9b, NR.sup.9 C(O)OR.sup.10, NR.sup.9 C(O)R.sup.10, .dbd.O, OR.sup.10, SR.sup.10, --CF3, COR.sup.10, CO.sub.2 R.sup.10, CONR.sup.9 R.sup.9a, NHC(O)NR.sup.9 R.sup.9a, NHC(S)NR.sup.9 R.sup.9a, SO.sub.2 NR.sup.9 R.sup.9a, SO.sub.2 R.sup.10, C.sub.3-10 carbocycle substituted with 0-5 R.sup.11, and 5-10 membered heterocycle substituted with 0-3 R.sup.11 ; PA1 R.sup.9 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; PA1 R.sup.9a is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; PA1 R.sup.9b is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; PA1 R.sup.10 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, benzyl; and PA1 R.sup.11 is, at each occurrence, independently selected from the group consisting of: selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.18 R.sup.18a, NR.sup.18 NR.sup.18a R.sup.18b, NR.sup.18 C(O)OR.sup.17, NR.sup.18 C(O)R.sup.17, .dbd.O, OR.sup.17, SR.sup.17, COR.sup.17, CO.sub.2 R.sup.17, CONR.sup.18 R.sup.18a, NHC(O)NR.sup.18 R.sup.18a, NHC(S)NR.sup.18 R.sup.18a, SO.sub.2 NR.sup.18 R.sup.18a, SO.sub.2 R.sup.17, C.sub.3-10 carbocycle substituted with 0-5 R.sup.19, and 5-10 membered heterocycle substituted with 0-3 R.sup.19. PA1 R.sup.2 is C.sub.1-4 alkyl substituted with 0-3 R.sup.7, C.sub.2-4 alkenyl substituted with 0-3 R.sup.7, C.sub.2-4 alkynyl substituted with 0-3 R.sup.7, --CF.sub.3, C.sub.3-6 carbocycle substituted with 0-5 R.sup.8, or 3-7 membered heterocycle substituted with 0-5 R.sup.8. PA1 R.sup.2 is C.sub.1-4 alkyl substituted with 0-3 R.sup.7, C.sub.2-4 alkenyl substituted with substituted with 0-3 R.sup.7, C.sub.2-4 alkynyl substituted with 0-3 R.sup.7, --CF.sub.3, C.sub.3-6 carbocycle substituted with 0-5 R.sup.8, or 5-7 membered heterocycle substituted with 0-5 R.sup.8. PA1 R.sup.2 is C.sub.3-6 saturated carbocycle substituted with 0-5 R.sup.8, or 5-7 membered saturated heterocycle substituted with 0-5 R.sup.8. PA1 R.sup.2 is C.sub.5-6 partially saturated carbocycle substituted with 0-5 R.sup.8, or 5-7 membered partially saturated heterocycle substituted with 0-5 R.sup.8. PA1 R.sup.2 is phenyl substituted with 0-5 R.sup.8, naphthyl substituted with 0-5 R.sup.8 or or 5-6 membered aromatic heterocycle heterocycle substituted with 0-5 R.sup.8. PA1 R.sup.2 is phenyl substituted with 0-3 R.sup.8, naphthyl substituted with 0-3 R.sup.8 or or 5-6 membered aromatic heterocycle heterocycle substituted with 0-3 R.sup.8. PA1 R.sup.2 is C.sub.3-6 carbocycle substituted with 0-5 R.sup.8, or 5-7 membered heterocycle substituted with 0-5 R.sup.8 ; PA1 R.sup.8 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14,--CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.8s are attachd to two adjacent carbon atoms, the two R.sup.8s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; and PA1 R.sup.13 R.sup.13a, and R.sup.13b are are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; or PA1 R.sup.13 and R.sup.13a, together with the nitrogen atom to which they are attached, form a 5-7 membered heterocycle substituted with 0-3 R.sup.16. PA1 R.sup.2 is C.sub.3-6 carbocycle substituted with 0-5 R.sup.8, or 5-7 membered heterocycle substituted with 0-5 R.sup.8 ; PA1 R.sup.8 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14,--CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, SO.sub.2 R.sup.14, C.sub.3-10 carbocycle substituted with 0-5 R.sup.15, and 5-10 membered heterocycle substituted with 0-3 R.sup.15, or when two R.sup.8s are attachd to two adjacent carbon atoms, the two R.sup.8s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; PA1 R.sup.13 R.sup.13a, and R.sup.13b are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; and PA1 R.sup.15 is, at each occurrence, independently selected from the group consisting of: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.20 R.sup.20a, NR.sup.20b NR.sup.20 R.sup.20a, NR.sup.20 C(O)OR.sup.21, NR.sup.20 C(O)R.sup.21, .dbd.O, OR.sup.21, SR.sup.21, COR.sup.21, CO.sub.2 R.sup.21, CONR.sup.20 R.sup.20a, NHC(O)NR.sup.20 R.sup.20a, NHC(S)NR.sup.20 R.sup.20a, SO.sub.2 NR.sup.20 R.sup.20a, and SO.sub.2 R.sup.21, or when two R.sup.15s, are attachd to two adjacent carbon atoms, the two R.sup.15s may combine to form --OCH20O-- or --OCH2CH2O--.
A series of 1-(6'-substituted-4'-methylquinol-2'-yl)-3-methylindeno[1,2-c]pyrazoles having CNS activity are described by Quraishi, Farmaco 44:753-8, 1989 with the following generic structure: ##STR4##
Compounds of this series are not considered to be part of the presently claimed invention.